This thesis describes water proton and deuterium relaxation processes, as seen by Nuclear Magnetic Resonance (NMR) spectroscopy, using Brownian Dynamics (BD) or Molecular Dynamics (MD) simulations. The MD simulations reveal new detailed information about the dynamics and order of water molecules outside of a lipid bilayer. This is very important information in order to fully understand deuterium NMR measurements in lipid bilayer systems, which require an advanced analysis, because of the complicated water motion (such as tumbling and self-diffusion). The BD simulation methods are combined with the powerful Stochastic Liouville Equation (SLE) in its Langevin form (SLEL) to give new insight into both 1H2O and 2H2O relaxation. The new simulation techniques which combine BD and SLEL can give important new information in cases where other methods do not apply. The deuterium relaxation is described in the context of a water/lipid interface and is in a very elegant way combined with the simulation of diffusion on curved surfaces developed by our research group. 1H2O spin-lattice relaxation is described for paramagneticsystems. With this we mean systems with paramagnetic transition metal ions or complexes, that are dissolved into a water solvent. The theoretical description of such systems are quite well investigated but such systems are not yet fully understood. An important consequence of the Paramagnetic Relaxation Enhancement (PRE) calculations when using the SLEL approach combined with BD simulations is that we obtain the electron correlation functions, which describe the relaxation of the paramagnetic electron spins. This means for example that it is also straight forward to generate Electron Spin Resonance (ESR) lineshapes.

Relaxation models are developed using numerical solutions of the Stochastic Liouville Equation of motion. Simplified descriptions such as the stochastic master equation is described in the context of fluorescence depolarisation experiments. Redfield theory is used in order to describe NMR relaxation in bicontinuous phases. The stochastic fluctuations in the relaxation models are accounted for using Brownian Dynamics simulation technique. A novel approach to quantitatively analyse fluorescence depolarisation experiments and to determine intramolecular distances is presented. A new Brownian Dynamics simulation technique is developed in order to characterize translational diffusion along the water lipid interface of bicontinuous cubic phases.

No description available.

The transport of a biomolecule through a nanopore occurs in many biological functions such as, DNA or RNA transport across nuclear pores and the translocation of proteins across the eukaryotic endoplasmic reticulum. In addition to the biological processes, it has potential applications in technology such as, drug delivery, gene therapy, and single molecule sensing. The DNA translocation through a synthetic nanopore device is considered as the basis for cheap and fast sequencing technology. Motivated by the experimental advances, many theoretical models have been developed. In this thesis, we explore the dynamics of driven translocation of a semiflexible polymer through a nanopore in two dimensions (2D) using Langevin dynamics (LD) simulation. By carrying out extensive simulation as a function of different parameters such as, driving force, length and rigidity of the chain, viscosity of the solvent, and diameter of the nanopore, we provide a detailed description of the translocation process. Our studies are relevant for fundamental understanding of the translocation process which is essential for making accurate nano-pore based devices.

No description available.

Electronic energy transfer has been investigated in pure donor systems by means of computer simulations. Calculated properties were the probability that the initially excited donor is excited at a time t after the excitation, Gs(t), the mean square displacement of the excitation and different fluorescence observables. For three dimensional systems the results obtained by Monte Carlo simulations were compared to the so-called GAF-theory {Gouchanour,C. R., Andersen, H. C. and Fayer, M. D., J. Chem. Phys. 81, 4380 (1984)}, and the agreement was found to be good. Anisotropic systems, i.e. mono-, bi- and multilayer systems, were compared to the two-particle model {Baumann,J. and Fayer, M. D., J. Chem. Phys. 85, 4087 (1986)}. The agreement between the Gs(t) calculated from the tp- model and the Monte Carlo simulations were good for all systems investigated. However, the agreement between the fluorescence observables obtained by MC and the tp-model were in general poor. A much better agreement was found when a phenomenological approach was used for calculating the fluorescence depolarization ratios. Three dimensional systems where the donors are rotating on the same time scale as the energy transfer takes place have also been studied and compared to analytical theories. The Molecular Dynamics simulations of decapeptide H142 shows that simulations in a continuum with a relative permeability do not provide a reliable alternative to simulations with explicit solvent molecules. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1991, härtill 5 uppsatser</p> / digitalisering@umu

Dans le cadre d’un projet de drug design, l’amélioration de la prédiction de l’affinité représente toujours un défi malgré les nombreux efforts déployés dans ce sens. De plus, les constantes cinétiques d’association et de dissociation sont d'un intérêt majeur pour la découverte de nouveaux médicaments, notamment au stade précoce de l'optimisation des molécules afin de mieux évaluer leurs tolérances et efficacités. De par la récente émergence des études de constantes cinétiques, il existe peu de méthodes de prédiction de ces dernières et aucune approche efficace n'a encore été développée pour estimer correctement ces paramètres cinétiques.En relevant ces deux défis, le premier volet de cette thèse consiste au développement de nouvelles méthodes qui permettent dans un premier temps d’améliorer la prédiction de l’affinité par docking flexible et dans un deuxième temps la prédiction des constantes cinétiques d’association et de dissociations (kon et koff) grâce à des simulations de dynamique moléculaire accélérées.Dans le second volet de cette thèse, nous avons conçu de nouveaux inhibiteurs des LIM kinases, cibles émergentes impliquées dans plusieurs physiopathologies incluant la neurofibromatose et le cancer. Nos composés ont de bonnes affinités et sélectivités in vitro, et d’excellentes activités et tolérances évaluées sur des tests cellulaires. / In a drug design project, improving the prediction of affinity is still an issue despite the considerable efforts made in this direction. In addition, binding kinetic constants are of major interest for the discovery of new drugs, in particular at the early stage of molecules optimization to better evaluate their tolerance and efficacy. Due to the recent emergence of the importance of binding kinetics, methods of kinetic rates prediction remain scarce and no efficient computational approach has still been developed to correctly estimate kinetic parameters.In order to challenge these two problematics, the first part of this thesis consists in the development of new methods that allow, first, to improve the prediction of affinity by a flexible docking and, second, to predict the ligand binding/unbinding pathways and binding kinetic rates (kon and koff) by enhanced molecular dynamics simulations.In the second part of this thesis, we have designed novel inhibitors of LIM kinases, emerging targets involved in several pathophysiologies including neurofibromatosis and cancer. Our compounds have good affinities and selectivities in vitro, and excellent activities and tolerances evaluated on cellular tests.

Neben ihrer Bedeutung in industriellen Anwendungen dienen Kolloide als Modellsysteme in Experimenten und in der Theorie, um die Struktur und Dynamik von kondensierter Materie zu untersuchen. Kürzlich wurde experimentell gezeigt, dass eine kleine Anisotropie ausreicht, um die viskoelastische Antwort im Vergleich zu harten Kugeln drastisch zu ändern. Die mikroskopischen Ursachen hierfür sind bisher nicht verstanden. In dieser Arbeit werden daher Nichtgleichgewichts-Brownsche-Dynamik-Simulationen (NEBD) von harten kolloidalen Dumbbells in oszillatorischen Scherfeldern entwickelt und eingesetzt, um diese Resultate mit Verbindung zu Rheologie- und Neutronenstreuexperimenten zu erklären. Weiterhin wird die Bedeutung der Anisotropie für Struktur und Dynamik von solchen Suspensionen im Gleichgewicht mit Hilfe von "Linear-Response"-Theorie und Brownsche-Dynamik-Simulationen analysiert. Im linearen Limit zeigt die Scherviskosität bei hohen Packungsdichten einen dramatischen Anstieg jenseits eines kritischen Anisotropieparameters. Dies weist darauf hin, dass schon bei den kleinen Anisotropien kollektive Rotations-Translations-Kopplungen für langsame Zeitskalen verantwortlich sind. Weiterhin wird ein Nichtgleichgewichtsübergang mittels NEBD-Simulationen von Suspensionen harter Dumbbells im PC unter oszillatorischer Scherung ersichtlich. Es wird gezeigt, dass der kontinuierliche Übergang nur für sehr kleine Aspektverhältnisse erhalten bleibt. Oberhalb eines bestimmten Aspektverhältnisses wird der Übergang durch einen ungeordneten Zustand vermittelt. Außerdem wird ein Sliding-Layer Zustand mit kollektiver Ordnung der Teilchenausrichtung bei hohen Scheramplituden beobachtet. Somit zeigt diese Arbeit, dass die NEBD-Simulationen Phänomene in Rheologie- und Streuexperimenten erklären. Angesichts dieser Experimente wird gezeigt, dass der Orientierungsfreiheitsgrad einen starken Einfluss auf den strukturellen Übergang bei steigenden Amplituden hat. / Besides being important for industrial applications, colloidal suspensions have long served as model systems for investigating the structure and dynamics of condensed matter. Recently, it has been demonstrated experimentally that apparently a small particle anisotropy is sufficient to dramatically change the viscoelastic response under external shearing fields, of which the microscopic mechanisms are not yet sufficiently understood. In the present work, NEBD simulations of colloidal hard dumbbells in oscillatory shear fields are developed and employed to elucidate the novel findings in close connection with comprehensive rheology and SANS experiments. Furthermore, by utilising BD simulations and linear response theory, the impact of anisotropy on structure and dynamics of such suspensions in equilibrium is analysed. In the linear response limit, the shear viscosity exhibits a dramatic increase at high packing fractions beyond a critical anisotropy of the particles. This indicates that newly occurring, collective rotational-translational couplings must be made responsible for slow time scales appearing in the PC. Moreover, a non-equilibrium transition emerging at moderate aspect ratios is revealed by NEBD of plastic crystalline suspensions under oscillatory shear. This transition behaviour is systematically studied. It is demonstrated that the continuous nature of the transition is retained for very low aspect ratios only. Above a certain aspect ratio, the transition is mediated by an intermediate disordered state. Furthermore, a partially oriented sliding layer state featuring a finite collective order in the particles'' orientations is observed at high strains. Hence, this thesis demonstrates that the NEBD simulations explain novel phenomena in rheology and scattering experiments. In the light of these experiments, it is shown that the orientational degree of freedom has a vigorous impact on the structural transition under increasing oscillatory shear.

Les nanocomposites polymères ont fait l'objet de recherches académiques et industrielles au cours des dernières décennies, du fait de leurs remarquables propriétés mécaniques et rhéologiques comparés aux polymères purs. En particulier, ils présentent du renforcement pour des fractions volumiques modérées, et des effets non linéaires pour des déformations relativement faibles. Malgré des décennies de recherche, la relation entre la rhéologie et la structure des nanocomposites est loin d'être comprise. Les simulations atomistiques peuvent donner une vision détaillée de l'interaction entre la dynamique des chaînes polymères et les charges renforçantes à une échelle locale. Cependant, il est difficile d'aborder les propriétés émergentes à une échelle mésoscopique, par exemple, simuler un grand nombre d'agrégats dans une matrice polymère enchevêtrée reste toujours hors de portée. Dans ce travail, nous proposons un modèle mésoscopique pour simuler la rhéologie des nanocomposites avec un fluide simple ou une matrice polymère enchevetrée, en utilisant la dynamique brownienne et la dynamique généralisée de Langevin, respectivement. Dans les deux dynamiques, le mouvement des chaines de polymère n'est pas décrit de façon explicite et son effet sur la dynamique de la charge est «moyenné». En utilisant ce modèle, nous étudions l'influence du type de charge, de leur taille, morphologie, et fraction volumique sur la rhéologie du composite modèle, ainsi que la morphologie des charges dans les simulations. Un cas particulièrement intéressant est celui d'agrégats quasi-fractals, qui peuvent être flexibles ou bien rigides. Nous démontrons que les systèmes avec agrégats présentent un renforcement significatif, qui augmente avec la taille des agrégats, leur rigidité, leur fraction volumique et leur polydispersité en taille. Une relaxation lente est également mise en évidence, et nous montrons qu'elle est liée à la rotation lente des agrégats. L'effet Payne, associé à la réponse non linéaire des modules dynamiques avec l'amplitude de déformation de cisaillement, est également observé pour nos modèles de composites. Nous faisons le lien entre l'arrangement microscopique des charges sous cisaillement et les propriétés macroscopiques du composite / Polymer nanocomposites have drawn a lot of attention both from the academic and industrial research in the last decades, thanks to their remarkable mechanical and rheological properties as compared to pure polymers. In particular, they may display reinforcement for moderate volume fractions, and several non linear effects that appear for small deformation amplitudes. In spite of decades of research, the relation between nanocomposites structure and rheology is far from being understood. Atomistic simulations can give a detailed view of the interplay between polymer chains dynamics and fillers at a local scale. However, it is much more difficult to address the properties emerging at a mesoscopic scale, for instance, to simulate a large number of aggregates in an entangled polymeric matrix remains out of reach. In this work, we build a mesoscopic model to simulate the rheology of polymer nanocomposites with a simple fluid and an entangled polymer matrix, by using the Brownian dynamics and the generalized Langevin dynamics, respectively. In both cases, the motion of the polymer chains is not explicitly described and its effect on the filler dynamics is "averaged out". Using this model, we quantitatively determine the influences of the filler type, the filler volume fraction, size and morphology on the rheology of the model composite. Of particular interest is the case of fractal-like aggregates, which may be flexible or rigid. We demonstrate that model aggregates display significant reinforcement, which increases with the aggregate size, aggregate rigidity, filler volume fraction and polydispersity. Long relaxation times are also evidenced, which are related to the slow rotation of the aggregates. The well-known Payne effect, associated to the nonlinear response of the dynamic moduli with the shear deformation amplitude, is also seen in our model composites. We relate the behavior of microscopic filler to the macroscopic properties of the composite

This thesis describes a project in which algorithms are developed for the rapid and accurate solution of Poisson's equation in the presence of a dielectric boundary and multiple point charges. These algorithms are then used to perform Brownian dynamics simulations on realistic models of biological ion channels. An iterative method of solution, in which the dielectric boundary is tiled with variable sized surface charge sectors, provides the flexibility to deal with arbitrarily shaped boundaries, but is too slow to perform Brownian dynamics. An analytical solution is derived, which is faster and more accurate, but only works for a toroidal boundary. Finally, a method is developed of pre-calculating solutions to Poisson's equation and storing them in tables. The solution for a particular configuration of ions in the channel can then be assembled by interpolation from the tables and application of the principle of superposition. This algorithm combines the flexibility of the iterative method with greater speed even than the analytical method, and is fast enough that channel conductance can be predicted. The results of simulations for a model single-ion channel, based on the acetylcholine receptor channel, show that the narrow pore through the low dielectric strength medium of the protein creates an energy barrier which restricts the permeation of ions. They further show that this barrier can be removed by dipoles in the neck of the channel, but that the barrier is not removed by shielding by counter-ions. The results of simulations for a model multi-ion channel, based on a bacterial potassium channel, show that the model channel has conductance characteristics similar to those of real potassium channels. Ions appear to move through the model multi-ion channel via rapid transitions between a series of semi-stable states. This observation suggests a possible physical basis for the reaction rate theory of channel conductance, and opens up an avenue for future research.